烟酰胺核苷氯化物对改善酒精诱导的神经元损伤的治疗作用，重点是线粒体未折叠蛋白反应和线粒体吞噬
The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.
摘要(中文译文)
过量饮酒会导致神经退行性变，其主要驱动因素是氧化应激和线粒体功能障碍，但目前尚无特异性治疗方法。烟酰胺核糖氯化物（NRC）作为烟酰胺腺嘌呤二核苷酸前体，已在改善心力衰竭中的线粒体功能障碍方面显示出治疗潜力，但其在酒精诱导的神经退行性变中的作用尚未被探索。本研究通过行为学测试、血清乙醇和炎症标志物分析、苏木精-伊红染色以及模型的分子学检测，探讨了NRC的神经保护作用。蛋白质组学和GEO数据库分析进一步阐明了酒精诱导脑损伤的机制。结果显示，NRC显著改善了酒精相关的认知障碍和神经炎症。我们的实验数据和外部数据集均发现，线粒体功能障碍是酒精诱导神经元损伤的关键驱动因素，其特征为线粒体自噬受损和线粒体未折叠蛋白反应（UPR）紊乱。补充NRC通过增强UPR和Fundc1依赖性线粒体自噬恢复了线粒体稳态。机制上，抑制UPR通过抑制Fundc1表达和线粒体自噬消除了NRC的保护作用，而抑制线粒体自噬不影响UPR，提示存在UPR调控Fundc1介导的线粒体自噬的层级调节关系。总之，酒精会破坏线粒体质量控制，但NRC通过激活UPR并恢复Fundc1驱动的线粒体自噬来对抗神经元毒性，为酒精相关神经元损伤提供了一种有前景的治疗策略。
Abstract
Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC's neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPR). NRC supplementation restored mitochondrial homeostasis by enhancing UPR and Fundc1-dependent mitophagy. Mechanistically, UPR inhibition abolished NRC's protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPR, suggesting a hierarchical regulation where UPR governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPR and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.
如何引用
AMA
Jinyang Wang, Jianan Wang, Wei Xie, Qi Shen, Chengbin Wang, Ruibing Li, et al. The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.. Genes & diseases. 2026; doi:10.1016/j.gendis.2025.101886.
APA
Jinyang Wang, Jianan Wang, Wei Xie, Qi Shen, Chengbin Wang, Ruibing Li, et al (2026). The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.. Genes & diseases. https://doi.org/10.1016/j.gendis.2025.101886
GB/T 7714
Jinyang Wang, Jianan Wang, Wei Xie, Qi Shen, Chengbin Wang, Ruibing Li, et al. The therapeutic effect of nicotinamide riboside chloride on ameliorating alcohol-induced neuronal damage with a focus on mitochondrial unfolded protein response and mitophagy.[J]. Genes & diseases, 2026 doi:10.1016/j.gendis.2025.101886.
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